We have more than 1000 long-term survivors of childhood cancer followed in our Late Effects and Neuro-Oncology Clinics. With improved treatment modalities, more patients diagnosed with childhood cancer are surviving into adulthood. Endocrine and cardiovascular late effects have been described by our group and others in long-term survivors of childhood cancer. This includes obesity and the Metabolic Syndrome (1-8). The atherosclerotic cardiovascular disease component of the Metabolic Syndrome continue to be one of the leading cause of death in the general population and may occur earlier and with increased frequency in survivors of childhood cancer. Obesity is major component of the Metabolic Syndrome. There is little information on the mechanism of obesity in long-term cancer survivors. This project is a pilot study to determine the role of neuropeptides in the development of obesity in cancer survivors treated with cranial irradiation with or without surgery. We plan to enroll obese cancer survivors and perform a 2-hr oral glucose tolerance test (OGTT) measuring glucose, insulin and obesity-related peptides levels. We hypothesize that childhood cancer survivors exposed to cranial irradiation and/or cranial surgery experience disruption in the hypothalamus that increases the risk for the development of hypothalamic obesity and insulin resistance, both components of the Metabolic Syndrome many years after completion of therapy. Obese survivors with these treatments will have abnormal levels of obesity-related peptides compared to obese survivors without those treatments. Among obese survivors, the proportion of insulin resistant patients is higher among those who had cranial irradiation and/or cranial surgery and who also have abnormal levels of the obesity-related peptides. A successful conclusion to this project will not only result in the development of preventive and intervention therapy to minimize the cardiovascular risks in these patients but also open the way to more focused studies of neuropeptide involvement in the pathogenesis of osteopenia/osteoporosis, a less well-described but recently recognized to have a higher incidence in long-term survivors of childhood cancers (22).